© 2015 Wiley Periodicals, Inc.
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PERIOPERATIVE MANAGEMENT_____________________________________________________
Low Molecular Weight Heparin (LMWH)–Induced Bullous Hemorrhagic Dermatosis Serkan Burc Deser, M.D., and Mustafa Kemal Demirag, M.D. Department of Cardiovascular Surgery, 19 Mayis University, Faculty of Medicine, Samsun, Turkey ABSTRACT Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are associated with side effects including hematomas, skin necrosis, contact dermatitis, and urticaria. We present a patient awaiting bypass surgery who developed bullous hemorrhagic dermatosis following LMWH. doi: 10.1111/jocs.12558
(J Card Surg 2015;30:568–569) Low molecular weight heparin (LMWH) is widely used in the treatment of acute coronary syndromes and venous thromboembolism.1 Heparin-induced skin necrosis (HISN) is a rare but potentially fatal adverse reaction that is associated with heparin use. It was first described by O’Toole in 1973.2 Since then, skin necrosis has been reported after intravenous and subcutaneous administration of LMWHs and UFH. HISN typically develops with painful erythematous lesions on the injection site within days to weeks of initiating treatment. The lesions frequently occur at the sites of heparin injection, but involvement at distant sites has also been reported. Skin necrosis may be related to the thrombosis of dermal capillary vessels and heparin-platelet factor 4 (HPF4) antibodies. PATIENT PROFILE A 71-year-old male with a history of ischemic heart disease was hospitalized for stable angina. Coronary angiography revealed significant lesions involving the left anterior descending and circumflex coronary arteries. He was prepared for coronary artery bypass grafting surgery. He received LMWH enoksaparin sodium 6,000 anti-Xa/0.6 mL (clexane, Sanofi aventis, Paris, France) twice daily by subcutaneous injections. Two days following LMWH therapy, an initial painful
Conflict of interest: The authors declared no conflicts of interest with respect to the research and/or authorship of this article. The authors received no financial support for the research and/or authorship of this article. Address for correspondence: Serkan Burc Deser, M.D., Department of Cardiovascular Surgery, 19 Mayis University, Faculty of Medicine, 55139 Samsun, Turkey. Fax: 00903624576091; e-mail: sbd983@ yahoo.com
bullous stage followed by well-circumscribed areas of skin lesions developed in his abdomen (Fig. 1). Physical examination revealed tense hemorrhagic bullae on otherwise normal skin. Mucous membranes were normal and there was no pruritus. Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen levels, fibrin degradation products, and D dimers were normal. Blood cell count including platelet count, urea and electrolyte levels, and liver function tests were also normal. LMWH was discontinued and was associated with a decrease in erythema and improvement in the patients lesion. One week after discontinuing the treatment, the skin lesion dried out and peeled spontaneously (Fig. 2). After exclusion of heparin-induced thrombocytopenia (HIT), we performed surgery two weeks after the first lesion occurred. Initial anticoagulation was provided with UFH. No complication was seen during and after the surgery. Institutional review board permission was not required to report this case. DISCUSSION Bullae can also be associated with furosemide, e-aminocaproic acid, and phenylbutazone. HISN is associated with heparin-platelet factor (HPF4) complex, even in the absence of thrombocytopenia. However, histological examination failed to demonstrate dermal capillary thrombosis so the pathogenic role of these antibodies is unlikely. It is thought that the skin necrosis occurs due to a type III hypersensitivity reaction in which antigen antibody complexes are deposited in the skin blood vessels. These antibodies may lead to platelet activation and thrombus formation inside the vessels, leading to bullous formation and necrosis. Warkentin reported six patients with HISN who
J CARD SURG 2015;30:568–569
DESER AND DEMIRAG LOW MOLECULAR WEIGHT HEPARIN
569
Figure 1. Bullous hemorrhagic dermatosis on site of abdomen.
developed heparin-dependent platelet activating immunoglobulin G antibodies typically seen in heparininduced thrombocytopenia (HIT).3 However, thrombocytopenia was seen only in two patients. White et al. reported six patients with skin necrosis and demonstrated heparin-induced platelet aggregation in vitro in five patients.4 HISN is not only diagnosed by clinical findings but also by histologic assays. The most common histologic findings are epidermal necrosis with thrombi of the dermal blood vessels and variable amounts of inflammation. Attention must be paid to recognize HISN as soon as possible so that the offending medication can be discontinued. A delay in diagnosis may lead to serious morbidity and mortality. Arterial and venous thromboembolic complications have been reported. Patients with preexisting coagulopathic disorders—such as protein C or protein S deficiency and antiphospholipid syndrome—may be at higher risk for serious adverse events. Lesions often heal within several weeks. Surgical debridement and skin grafting may also be necessary. Patients should avoid all heparin products and switch to alternative forms of heparin after HIT is excluded. The absolute risk for HIT with LMWH was 0.2% and the mortality rate of HIT is estimated to be as high as 33%.5 Direct thrombin inhibitors such as lepirudin, argatroban, and bivalirudin
Figure 2. Healing of the lesion.
may be used instead of heparin. We believe that patient may proceed with surgery after the lesions have been healed and HIT has been excluded. In the present case, it was only after HIT was excluded that we performed the surgery using UFH.
REFERENCES 1. Tietge UJ, Schmidt HH, Jackel E, et al: Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia. Intern Med 1998;243:313–315. 2. O’Toole RD: Heparin: Adverse reaction. Ann Intern Med 1973;79:759. 3. Warkentin TE, Roberts RS, Hirsh J, et al: Heparin-induced skin lesions and other unusual sequelae of the heparininduced thrombocytopenia syndrome: A nested cohort study. Chest 2005;127:1857–1861. 4. White PW, Sadd JR, Nensel RE: Thrombotic complications of heparin therapy: Including six cases of heparin-induced skin necrosis. Ann Surg 1979;190:595–608. 5. Martel N, Lee J, Wells PS: Risk for heparin-induced thrombocytopenia with unfractionated and low-molecularweight heparin thromboprophylaxis: A meta-analysis. Blood 2005;106(8):2710–2715.
568
PERIOPERATIVE MANAGEMENT_____________________________________________________
Low Molecular Weight Heparin (LMWH)–Induced Bullous Hemorrhagic Dermatosis Serkan Burc Deser, M.D., and Mustafa Kemal Demirag, M.D. Department of Cardiovascular Surgery, 19 Mayis University, Faculty of Medicine, Samsun, Turkey ABSTRACT Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are associated with side effects including hematomas, skin necrosis, contact dermatitis, and urticaria. We present a patient awaiting bypass surgery who developed bullous hemorrhagic dermatosis following LMWH. doi: 10.1111/jocs.12558
(J Card Surg 2015;30:568–569) Low molecular weight heparin (LMWH) is widely used in the treatment of acute coronary syndromes and venous thromboembolism.1 Heparin-induced skin necrosis (HISN) is a rare but potentially fatal adverse reaction that is associated with heparin use. It was first described by O’Toole in 1973.2 Since then, skin necrosis has been reported after intravenous and subcutaneous administration of LMWHs and UFH. HISN typically develops with painful erythematous lesions on the injection site within days to weeks of initiating treatment. The lesions frequently occur at the sites of heparin injection, but involvement at distant sites has also been reported. Skin necrosis may be related to the thrombosis of dermal capillary vessels and heparin-platelet factor 4 (HPF4) antibodies. PATIENT PROFILE A 71-year-old male with a history of ischemic heart disease was hospitalized for stable angina. Coronary angiography revealed significant lesions involving the left anterior descending and circumflex coronary arteries. He was prepared for coronary artery bypass grafting surgery. He received LMWH enoksaparin sodium 6,000 anti-Xa/0.6 mL (clexane, Sanofi aventis, Paris, France) twice daily by subcutaneous injections. Two days following LMWH therapy, an initial painful
Conflict of interest: The authors declared no conflicts of interest with respect to the research and/or authorship of this article. The authors received no financial support for the research and/or authorship of this article. Address for correspondence: Serkan Burc Deser, M.D., Department of Cardiovascular Surgery, 19 Mayis University, Faculty of Medicine, 55139 Samsun, Turkey. Fax: 00903624576091; e-mail: sbd983@ yahoo.com
bullous stage followed by well-circumscribed areas of skin lesions developed in his abdomen (Fig. 1). Physical examination revealed tense hemorrhagic bullae on otherwise normal skin. Mucous membranes were normal and there was no pruritus. Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen levels, fibrin degradation products, and D dimers were normal. Blood cell count including platelet count, urea and electrolyte levels, and liver function tests were also normal. LMWH was discontinued and was associated with a decrease in erythema and improvement in the patients lesion. One week after discontinuing the treatment, the skin lesion dried out and peeled spontaneously (Fig. 2). After exclusion of heparin-induced thrombocytopenia (HIT), we performed surgery two weeks after the first lesion occurred. Initial anticoagulation was provided with UFH. No complication was seen during and after the surgery. Institutional review board permission was not required to report this case. DISCUSSION Bullae can also be associated with furosemide, e-aminocaproic acid, and phenylbutazone. HISN is associated with heparin-platelet factor (HPF4) complex, even in the absence of thrombocytopenia. However, histological examination failed to demonstrate dermal capillary thrombosis so the pathogenic role of these antibodies is unlikely. It is thought that the skin necrosis occurs due to a type III hypersensitivity reaction in which antigen antibody complexes are deposited in the skin blood vessels. These antibodies may lead to platelet activation and thrombus formation inside the vessels, leading to bullous formation and necrosis. Warkentin reported six patients with HISN who
J CARD SURG 2015;30:568–569
DESER AND DEMIRAG LOW MOLECULAR WEIGHT HEPARIN
569
Figure 1. Bullous hemorrhagic dermatosis on site of abdomen.
developed heparin-dependent platelet activating immunoglobulin G antibodies typically seen in heparininduced thrombocytopenia (HIT).3 However, thrombocytopenia was seen only in two patients. White et al. reported six patients with skin necrosis and demonstrated heparin-induced platelet aggregation in vitro in five patients.4 HISN is not only diagnosed by clinical findings but also by histologic assays. The most common histologic findings are epidermal necrosis with thrombi of the dermal blood vessels and variable amounts of inflammation. Attention must be paid to recognize HISN as soon as possible so that the offending medication can be discontinued. A delay in diagnosis may lead to serious morbidity and mortality. Arterial and venous thromboembolic complications have been reported. Patients with preexisting coagulopathic disorders—such as protein C or protein S deficiency and antiphospholipid syndrome—may be at higher risk for serious adverse events. Lesions often heal within several weeks. Surgical debridement and skin grafting may also be necessary. Patients should avoid all heparin products and switch to alternative forms of heparin after HIT is excluded. The absolute risk for HIT with LMWH was 0.2% and the mortality rate of HIT is estimated to be as high as 33%.5 Direct thrombin inhibitors such as lepirudin, argatroban, and bivalirudin
Figure 2. Healing of the lesion.
may be used instead of heparin. We believe that patient may proceed with surgery after the lesions have been healed and HIT has been excluded. In the present case, it was only after HIT was excluded that we performed the surgery using UFH.
REFERENCES 1. Tietge UJ, Schmidt HH, Jackel E, et al: Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia. Intern Med 1998;243:313–315. 2. O’Toole RD: Heparin: Adverse reaction. Ann Intern Med 1973;79:759. 3. Warkentin TE, Roberts RS, Hirsh J, et al: Heparin-induced skin lesions and other unusual sequelae of the heparininduced thrombocytopenia syndrome: A nested cohort study. Chest 2005;127:1857–1861. 4. White PW, Sadd JR, Nensel RE: Thrombotic complications of heparin therapy: Including six cases of heparin-induced skin necrosis. Ann Surg 1979;190:595–608. 5. Martel N, Lee J, Wells PS: Risk for heparin-induced thrombocytopenia with unfractionated and low-molecularweight heparin thromboprophylaxis: A meta-analysis. Blood 2005;106(8):2710–2715.
